This proposal requests renewed funding to continue our productive investigations on the Pathophysiology of Type 2 Diabetes in Youth. During the previous cycle we studied the role of insulin resistance and beta-cell secretion in the earliest stage of T2DM, namely: Impaired Glucose Tolerance (IGT). Recent studies by our group have established a strong relationship between fatty liver, prediabetes and T2DM in obese adolescents. Of note, our group has described the longitudinal trajectories in both insulin resistance, beta-cell function and Disposition Index during the transition from NGT to IGT, over a 3 year period in obese adolescents. We found that those who progressed to IGT already had pre-existing defects in beta-cell glucose responsivity at baseline (by the Oral Minimal Model). This series of studies led to our central hypothesis that prior to the onset of IGT or T2DM in youth, inherent genetic variants might be linked to beta-cell dysfunction which will worsen over a relatively short period of time due to the worsening of insulin resistance secondary to the accumulation of lipids in muscle and liver (NAFLD/NASH). Accordingly, we propose to search for genetic determinants of beta-cell defects that we have identified, using detailed phenotyping combined with genotyping of polymorphisms (SNPs) related to beta-cell function. To accomplish this goal we have created an interdisciplinary team of world-renowned scientists at Yale, and in Europe, spanning the breadth from Clinical science (Pediatrics, Epidemiology) and Basic science (Genetics, Bioinformatics). The specific aims are: Aim 1: A) To examine the relationships between a panel of 16 gene variants (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, HHEX, CDC123/CAMK1D, WFS1, TSPAN8/LGR5, THADA, ADAMTS9) and measures of beta-cell function in obese adolescents with a wide distribution of the DI, using the Oral Minimal Model. B) To longitudinally test the individual and cumulative effects of diabetes risks alleles on measures of beta-cell function in non- diabetic obese adolescents across the spectrum of DI, using the Oral Minimal Model. Aim 2: A) To determine longitudinally whether adiponectin (total and/or HMW) is associated with hepatic fat accumulation determined by Fast-MRI. B) To determine if circulating adiponectin levels, total and/or the HMW form, distinguish simple hepatic steatosis from steatohepatitis (NASH), and whether it might act as a biomarker of NASH, determined by biopsy. Ultimately, the results of this project will be crucial in attaining our long term goals of (a) understanding the fundamental causes(s) of T2DM in youth and (b) developing strategies to predict and prevent the disease and its complications. PUBLIC HEALTH RELEVANCE: Type 2 Diabetes in obese youth is often preceded by a prediabetic state called: Impaired Glucose Tolerance (IGT) and hepatic steatosis. Importantly, obese adolescents with IGT have pre-existing defect in insulin secretion. We will determine here if genetic factors are associated with defects in insulin secretion in a large cohort of obese children and adolescents and assess if the simple measure of circulating adiponectin may function as a biomarker of hepatic fat accumulation. Our long term goal is to generate information on both the genetics as well as the pathophysiology of Type 2 Diabetes in Youth, which ultimately might guide us towards better preventive and treatment avenues.